The principal goal of the studies proposed in this application is to identify and to characterize the biosynthetic steps and molecular species involved in the production of the peptide neurotransmitter candidate substance P, using the basal ganglia as a model. By using an in vivo amino acid labeling paradigm and peptide chemistry methods, the applicant has been able to demonstrate de novo biosynthesis of radiolabeled substance P in the corpus striatum of individual unrestrained rats and its axonal transport to the substantia nigra. These studies will be extended in order to examine the dynamics of the in vivo biosynthesis and axonal transport of striatonigral substance P and its regulation. A substance P precursor protein will be isolated in axoplasmic transport studies using immunological, protein chemical and peptide mapping methods. These experiments will be extended to the identification of striatal messenger RNA molecule that codes for the substance P precursor proteins. The substance primary protein translation product will be studied by using striatal mRNA and cell-free translation techniques and immunoprecipitation and protein chemistry methods. These studies will provide a basis for investigating whether aberrations in the biosynthesis and processing in peptidergic neurons are responsible for, or associated with, neurodegenerative and psychiatric disorders in which central nervous system peptides are implicated. As such, these studies will provide a better understanding of basal ganglia substance P neurons and their reported relationship to the neurodegenerative diseases Parkinsonism and Huntington's chorea.